Although numerous advances have been made in the treatment of severe hemorrhage, current blood plasma substitutes do not address new insights in resuscitation medicine. Research in fluid technologies and vascular response following significant pre-hospital hemorrhage has identified several important characteristics that an optimal resuscitation fluid would possess. These include the ability to restore plasma volume, microcirculation, and oxygen delivery as well as practical items such as a low cost, low to no side effects, easy transportation, and storage. Conventional resuscitation fluids possess one or more limitations when compared to these ideal characteristics. The biocompatible, viscous, and oncotic biopolymer keratin is a potential solution to restore plasma volume while actually improving tissue oxygenation by recruitment of fluid into the vasculature and maintaining/improving hemodynamic parameters of microcirculation. The use of keratin in resuscitation fluids offers the potential to optimize a fluid that is compatible to the human circulatory microenvironment. Because of the flexible chemistry of keratin family of proteins, the physical, chemical, and biological properties of these materials can be controlled and optimized. By using chemical extraction techniques to preserve molecular weight and by formulating fluids to specific viscosities and oncotic pressures, optimal resuscitation fluids can be obtained. Purification strategies of these keratin fluids developed at the Wake Forest School of Medicine and licensed to KeraNetics have resulted in a fluid technology that, in rodent models, has solved many of the challenges with alternative resuscitation fluids. This fluid is based on a biocompatible keratin-based system that can be tuned to the hemodynamic needs of victims of severe hemorrhage/shock without the potential for thrombotic events or tissue damage. The keratin analogs are inexpensive to obtain (keratins can be extracted from human hair, which can be acquired for less than $3 per pound), can be sterilized using conventional techniques, and are shelf and temperature stable. Therefore, they can be stored at ambient temperatures (up to 50 degrees Celsius). Thus, keratin-based resuscitation fluids are potentially an ideal colloidal-based fluid for use by first responders. Data from the Phase I project determined that a specially formulated resuscitation fluid now called by the trade- name KeraStat is optimal and that this fluid has positive influence on hemodynamic recovery after hemorrhage/shock. Based on this data, we will test the hypothesis that KeraStat can restore normal cardiovascular performance and provide improved outcomes after hemorrhage/shock. This project will first examine the optimal keratin resuscitation fluid dosage/administration protocol in a rodent model. Using this protocol, we will then examine the effect of KeraStat on delayed treatment and long-term outcomes in a porcine model of trauma/hemorrhage/shock. These data will be instrumental in developing a preclinical data package to be submitted to the US Food and Drug Administration in support of clinical trials.